Triamcinolone acetonide derivative

ABSTRACT

Triamcinolone acetonide 4,4&#39;&#39;-methylene-bis(3-methoxy-2naphthoate), method of preparing the same by preparing a reactive derivative of 4,4&#39;&#39;-methylene-bis(3-methoxy-2-naphthoic) acid and reacting such derivative with triamcinoline acetonide. The triamcinolone acetonide derivative is particularly suitable for use in the treatment of dermatosis, eczema, neurodermatitis, impetigo, psoriasis, pruritis, erythema and the like.

United States Patent [1 1 Agusti Aug. 12, 1975 TRIAMCINOLONE ACETONIDEDERIVATIVE [75] Inventor:

[73] Assignee: J. Uriach & Cia S.A., Barcelona,

Spain 22 Filed: on. 1, 1974 211 Appl. No.: 511,075

, Related US. Application Data [62] Division of Ser. No. 452,322, Marchl8, 1974.

Agustin Agusti, Barcelona, Spain [52] US. Cl 424/241; 260/239.55 D [51]Int. Cl. A61K 17/00 [58] Field of Search 424/241; 260/239.55 D

Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Michael S.Striker [57] ABSTRACT Triamcinolone acetonide 4 ,4 '-methylene-bis( 3methoXy-2-naphthoate), method of preparing the same by preparing areactive derivative of 4,4- methylene-bis(3-methoxy-2-naphthoic) acidand reacting such derivative with triamcinoline acetonide. Thetriamcinolone acetonide derivative is particularly suitable for use inthe treatment of dermatosis, eczema, neurodermatitis, impetigo,psoriasis, pruritis, erythema and the like.

6 Claims, No Drawings TRIAMCINOLONE ACETONIDE DERIVATIVE This is adivision, of application Ser. No 452,322, filed 03/l8/74.

This invention relates to a new triamcinolone acetonide derivative, andmethods for making and using the same. More particularly the inventionrelates to triamcinolone' acetonide 4,4'-methylene-bis(3-methoxy-2-naphthoate) and the use thereof in treating a broad range ofdermatological conditions.

It is well known that triamcinolone acetonide, or 9afluoro-l 13,21-dihydroxy- 1 601,170!- isopropylidenedioxyl ,4-pregnadiene-3 ,ZO-dione,has proved particularly useful in the treatment of dermatologicalconditions. The compound has been proved to have marked efficacy in thetreatment of dermatosis, eczema, neurodermitis, impetigo, psoriasis,pruritis and other related diseases. However, in the long term topicaltreatment of large areas, especially with children and where there areskin lesions, there arise a great variety of general secondary reactionsdue to the percutaneous absorption of the corticoid. Thus the drug isknown to induce naturesis, negative sodium balance with weight loss inmost patients. Nearly every side effect seen with hydrocortisone hasbeen seen with triamcinolone acetonide but the relative frequencies areless. These undesirable results are particularly associated with longtherapy.

Triamcinolone acetonide is a fluorinated derivative of prednisone, thefluorine atom in the 9a position of the corticosteroid ring systemincreasing the activity of the glucocorticoid and reducing the action onthe metabolism of electrolytes.

Triamcinolone acetonide is the cyclic l6,l7acetal of triamcinolone withacetone and has the following formula:

c 14 on llac 0 The compound of the above formula is prepared by reactingtriamcinolone (9-fluoro-l l8, 1 6a, l 7,2 ltetrahydroxypregna-l,4-diene-3,20-dione) with acetone and perchloricacid followed by neutralization and vacuum concentration.

Triamcinolone can be synthesized from hydrocortisone acetate via the3,20-bis ketal by treatment with thionyl chloride, refluxing withpotassium hydroxide and acetylation to give 2 l-acetoxy-4,9,l l(l6)-pregnatriene-3.2()-dione. Oxidation with osmium tetroxide to theloa,l7wdihydroxy derivative and subscqucnt insertion of the )a-fluoroand l lB-hydroxy groups for instance by treatment with N-bromoacetamideand perchloric acid to give the 9a-bromo-l lBhydroxy compound followedby abstraction of HBr with potassium acetate to form the 9B,l lB-cpoxyderivative which by treatment with HF in a halogenated hydrocarbonyields the 9a-fluoro-l lB-hydroxy analog, gives a product lacking only adouble bond at the l-position. This latter step is accomplished byincubation with Norcardia corallina followed by saponification of theacetate to yield triamcinolone.

ln copending British application 38795/71 (now British Pat. No.1,332,058} a method has been described whereby the undesirable sideeffects of prednisone may be decreased or avoided by reacting theprednisone with an acid (particularly with an acid chloride) to form anester which has decreased or zero absorption with respect to prednisone.The new ester has the desired anti-inflammatory properties of prednisonebut may be administered without side effects resulting from absorptionwhen given topically, orally or by injection i.e., intramuscular orintravenous routes. The acid with which the prednisone is reacted is4,4-methylenebis( 3-methoxy-2-naphthoic) acid.

The preparation of the just-mentioned acid has been described in Spanishpatent application No. 385,254.

In accordance with the invention it has now been found thattriamcinolone acetonide 4,4-methylenebis(3-methoxy-2-naphthoate) whichis a new compound suitable for use in dermatological applications. It isintended for local application, in which circumstances it is moreefficaceous than triamcinolone and triamcinolone acetonamide and is morepotent. it is particularly adapted for use in the treatment of allergicand inflammatory dermatoses, pruritis, arthritis, bursititis, tendinitisand synovitis.

The naphthoate of the invention may be made by preparing a reactivederivative of 4,4-methylenebis(3methoxy-2-naphthoic) acid and therafterreacting the derivative with triamcinolone acetonide.

In the preparation of the naphthoate, the acid is preferably reactedwith a halogenating agent such as thionyl chloride to form two acidhalide moieties on the molecule i.e.

cox

ocs,

w coon I OCl l OCll C OOH where R is the radical of triamcinoloneacetonide.

As hydracid fixation agent, an organic base may be used. An example of aparticularly suitable base is pyridine, which acts both as base and as asolvent for the reaction.

The following Example is given in order to illustrate the invention butis in nowise to be construed as limitative thereof.

EXAMPLE Melting point Yield Elementary Analysis:

Calculated C 66.23% H 4.02% C1 15.64%

Found C 66.80% H 4.10% C1 15.66%

Grams of the acid chloride were treated with 19.2 gm of triamcinoloneacetonide in 150 ml pyridine. The mixture was heated for 3 hours at 90Cand the resultant solution added to 3 liters water. The product thusformed was recovered by filtration and was then washed with water. Itwas then vacuum dried at between 40C and 50C. Triamcinolone acetonide4,4- methylene bis(3-methoxy-2-naphthoate) was obtained in 90 percentyield.

After recrystallization from a mixture of acetone and water the productwas found to have the following properties:

Melting point 220C (decomposition) skin areas). In particular it wasdiscovered that oral administration of the product did not alterthe-urinary excretion rates of l7-ketosteroids, sodium or potassiumions, whereas these values changed significantly when related corticoidswere administered in the same dosages and under the same conditions.

However, other evaluating methods showed that the product of theinvention had the same anti-flammatory activity as triamcinoloneacetonide and was about 200 times as active as prednisone.

The compound may be administered in any suitable form together with apharmaceutically acceptable carrier. For example, for topicalapplication, it may suitably be made up in a concentration of 0.1 to 0.5percent and preferably of 0.3 percent in the form of a cream or pomade.When the cream is applied three times daily in the conventional mannerto affected areas, substantially total healing was reported in 100percent of cases having various dermatological diseases as for instancecontact dermatits and related allergies. eczema of physical, chemicaland medical origin. flexural and housewives eczema. impetigo, psoriasisand crythema, without any danger of secondary complaints cased byabsorption of the active material.

The lack of absorption provides a further advantage of the compound,namely that there is no danger of overdosages when the medicament isapplied to the skin or mucosa, or even from occlusive dressings ,applieddirectly onto affected areas.

The compound can be applied topically as a 0.1 percent solution, lotion,or aerosol or as a 0.1 to 0.5 percent cream applied 2 or 3 times daily.The compound can be administered intrasynovially, 2.5 to 15, mg as a 1percent suspension at intervals of l to several weeks. Orally thecompound is administered in amounts of 2 to 10 ml 3 to 4 times daily.

The lotion is made up in a suitable aqueous vehicle. The ointment ismade up in a suitable hydrophilic ointment base. The suspension is asterile suspension in a suitable aqueous medium.

An example of a hydrophilic base is hydrophilic petrolatum:

Cholesterol 30 grams Stearyl alcohol 30 grams White wax grams Whitepetrolatum 860 grams to make 1000 grams Another hydrophilic ointmentbase has the following composition:

Mcthylparabcn 0.25 grams Propylparaben 0.15 grams Sodium laurylsulfate10.00 grams Propylene glycol 120.00 grams Stearyl alcohol 250.00 gramsWhite petrolatum 250.00 grams Purified water 370.00 grams to make 1000grams The preparations, lotions, ointments or otherwise may furthercontain anesthetics, antiseptics, germicides, protective or screeningagents, pigments, etc.

I claim:

1. A pharmaceutical preparation comprising as active ingredienttriamcinolone acetonide 4,4- methylene-bis(3-methoxy-2-naphthoate); anda pharmaceutically acceptable carrier.

2. A pharmaceutical preparation according to claim 1 in the form of acream.

3. A pharmaceutical preparation according to claim 2 wherein said activeingredient is present in an amount of 0.1 to 0.5 percent.

4. A method of treating allergic and inflammatory dermatoses whichcomprises applying to affected areas of the skin a therapeuticallyeffective amount of a pharmaceutical preparation according to claim 1.

5. A method according to claim 4 which comprises applying saidpharmaceutical preparation as 0.1 to 0.5 percent cream 2 or 3 timesdaily.

6. A method of treating arthritis, bursitis, tendinitis and synovitiswhich comprises administering to the patient having such condition atherapeutically effective amount of a pharmaceutical preparationaccording to claim 1.

1. A PHARMACEUTICALLY PREPARATION COMPRISING AS ACTIVE INGREDIENTTRIAMCINOLONE ACETONIDE 4,4''-METHYLENE-BIS(3-METHYOXY2-NAPHTHOATE), ANDA PHARMACEUTICALLY ACCEPABLE CARRIER.
 2. A pharmaceutical preparationaccording to claim 1 in the form of a cream.
 3. A pharmaceuticalpreparation according to claim 2 wherein said active ingredient ispresent in an amount of 0.1 to 0.5 percent.
 4. A method of treatingallergic and inflammatory dermatoses which comprises applying toaffected areas of the skin a therapeutically effective amount of apharmaceutical preparation according to claim
 1. 5. A method accordingto claim 4 which comprises applying said pharmaceutical preparation as0.1 to 0.5 percent cream 2 or 3 times daily.
 6. A method of treatingarthritis, bursitis, tendinitis aNd synovitis which comprisesadministering to the patient having such condition a therapeuticallyeffective amount of a pharmaceutical preparation according to claim 1.